Naloxegol Oxalate and Solid Dispersion thereof

ABSTRACT

The present invention relates to solid dispersion of Naloxegol oxalate. Further, the present invention relates to an improved process for Naloxegol oxalate and intermediates thereof.

RELATED DOCUMENTS

This application is a contiuation of and claims priority from U.S.Application Ser. No. 16/462,856 filed on May 21, 2019 as a U.S. nationalapplication of international application PCT/IB2017/057325 filed on Nov.22, 2017 which claims priority from Indian applicataions IN201641039962filed Nov. 23, 2016 and IN201741022942 filed Jun. 30, 2017 andincorporates these prior applications by reference.

FIELD OF THE INVENTION

The present invention relates to solid dispersion of Naloxegol oxalate.Further, the present invention relates to a process for Naloxegoloxalate and intermediates thereof.

BACKGROUND OF THE INVENTION

Naloxegol is a PEGylated derivative of Naloxone. Naloxegol oxalate,chemically known as (5α,6α)-17-allyl-6-(2,5,8,11,14,17,20heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol oxalate and has astructure of formula I:

Naloxegol, which is marketed in the form of its oxalate salt is anopioid antagonist drug approved in United States and several othercountries under the trade name MOVANTIK®. Naloxegol oxalate is used inthe treatment of opioid-induced constipation (OIC) in adult patientswith chronic non-cancer pain.

U.S. Pat. No. 7,786,133 discloses Naloxegol and its pharmaceuticallyacceptable salts generically, and U.S. Pat. No. 9,012,469 disclosesspecifically Naloxegol oxalate and process for preparation thereof.

U.S. Pat. No. 9,012,469 describes crystalline Form A and Form B ofNaloxegol oxalate and process for the preparation thereof.

The occurrences of different solid forms are possible for somecompounds. A single compound may exist in different solid forms. Varioussolid forms of a drug substance can have different chemical and physicalproperties, including melting point, chemical reactivity, apparentsolubility, dissolution rate, optical and mechanical properties, vaporpressure, and density. These properties can have a direct effect on theability to process and/or manufacture the drug substance and the drugproduct, as well as on drug product stability, dissolution, andbioavailability. Thus, solid forms can affect the quality, safety, andefficacy of the drug product, regulatory authorities require thatefforts shall be made to identify all solid forms, e.g., crystalline,amorphous, solvated, etc., of drug substances.

Therefore, there is a need to develop amorphous Naloxegol oxalate, whichis stable, pure and industrially scalable.

U.S. Pat. No. 8,183,376 discloses a process for converting3-O-MEM-Naloxone to 3-O-MEM α-Naloxol by stereoselective reduction usingpotassium tri sec.-butylborohydride in presence of THF.

U.S. Pat. No. 7,786,133 discloses a process for preparing Naloxegol. Theprocess is depicted in the scheme-I:

The present inventors observed that the process of prior art gives3-O-MEM-Naloxone as thick viscous liquid which contains un-reactedreagents of the process as well as the process impurity, 3,14-di-O-MEMNaloxone:

These impurities are carried forward in subsequent steps to Naloxegol.These impurities generated during preparation of intermediates areundesirable and requires tedious purification processes, for example,column chromatography, at Naloxegol base.

Therefore, there is a need to develop an improved process for Naloxegol,which involves isolation of MEM-Naloxone and 3-O-MEM α-Naloxol or apharmaceutically acceptable salt thereof in solid form, and involvesselective purification for 3-O-MEM Naloxegol and Naloxegol to obtainpure Naloxegol Oxalate.

OBJECTIVE OF THE INVENTION

An objective of the present invention is to provide a solid dispersionof Naloxegol oxalate and an improved process for preparation ofNaloxegol oxalate.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a solid dispersion ofNaloxegol oxalate comprising Naloxegol oxalate in an amorphous and atleast one pharmaceutically acceptable carrier.

In another aspect, the present invention provides a process for thepreparation solid dispersion of Naloxegol oxalate, which comprises:

-   -   a) providing a solution of dissolving Naloxegol oxalate in a        solvent;    -   b) adding a pharmaceutically acceptable excipient; and    -   c) isolating amorphous solid dispersion of Naloxegol oxalate.

In another aspect, the present invention provides a process for thepurification of 3-O-MEM α-Naloxone, which comprises treatment of3-O-MEM-Naloxone with a base; and optionally isolating the solid of3-O-MEM-Naloxone having purity greater than 99% by HPLC.

In another aspect, the present invention provides a process for thepreparation of 3-O-MEM α-Naloxol, which comprises stereoselectivereduction of 3-O-MEM naloxone or salt thereof, with reducing agent inpresence of an additive and a solvent to provide 3-O-MEM α-Naloxolhaving α-epimer purity is greater than 99.7%.

In another aspect, the present invention provides a process for thepurification of 3-O-MEM α-Naloxol or salt thereof, which comprises:

-   -   a) treatment of 3-O-MEM α-Naloxol with an acid in a solvent to        provide acid addition salt of 3-O MEM; and    -   b) optionally, isolating the salt of 3-O-MEM α-Naloxol; and    -   c) treatment of the acid addition salt of 3-O-MEM α-Naloxol with        a base to provide 3-O-MEM α-Naloxol.

In another aspect, the present invention provides solid form of 3-O-MEMα-Naloxol salt of formula II and 3-O-MEM Naloxone of Formula III:

In another aspect, the present invention provides a process for thepurification of 3-O-MEM naloxegol having purity greater than or equal to95.5%, which comprises:

-   -   i) treating 3-O-MEM naloxegol with an acid to provide acid        addition salt of 3-O-MEM naloxegol;    -   ii) optionally isolating the acid addition salt of step (i);    -   iii) treating the acid addition salt of 3-O-MEM naloxegol with a        base to provide 3-O-MEM naloxegol;    -   iv) optionally, isolating 3-O-MEM naloxegol.

In another aspect, the present invention provides a process for thepurification of Naloxegol or salt thereof, which comprises:

-   -   i) treating Naloxegol with an acid to provide acid addition salt        of naloxegol;    -   ii) optionally, isolating the acid addition salt of Naloxegol;    -   iii) treating the acid addition salt of Naloxegol with a base to        provide pure Naloxegol or salt thereof.

In another aspect of the present invention, there is provided a processfor the preparation of compound of formula A:

wherein X is leaving group such as mesyl, tosyl, halo, nosyl whichcomprises:

-   -   a) condensation of triethyleneglycol monomethylether        monomesylate with tetraethylene glycolmonobenzyl ether to        provide heptaethylene glycol benzyl methyl ether;    -   b) conversion of the heptaethylene glycol benzyl methyl ether to        compound of formula A.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is X-ray power diffraction (“XRPD”) pattern of solid dispersionof Naloxegol oxalate prepared according to the present invention.

FIG. 2 is X-ray powder diffraction (“XRPD”) pattern of 3-O-MEM Naloxoneprepared according to example 3.

FIG. 3 is X-ray powder diffraction (“XRPD”) pattern of 3-O-MEM α-Naloxoloxalate prepared according to example 5.

DETAILED DESCRIPTION OF THE INVENTION

The “pure” of the present invention refers to, unless specifiedotherwise, that the compounds or salts thereof are having purity greaterthan about than about 98.0% or greater than about 99.5% by HPLC.Further, the “pure” refers to the material of present invention issubstantially free from impurities i.e. the impurities are less thanabout 1% or less than about 0.6% or less than about 0.3% by HPLCanalysis.

Furthermore, the present invention refers to “pharmaceuticallyacceptable salt” or “salt” or “HX” that may be obtained from inorganicacid or organic acid. The inorganic acid is selected from hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; theorganic acid may be selected from oxalic acid, acetic acid, maleic acid,succinic acid, methane sulfonic acid and the like, preferably the acidis oxalic acid.

The pure amorphous Naloxegol oxalate of the present invention have asuperior polymorphic purity is evident from perfect a single broaddiffraction peak (halo) in XRPD.

The amorphous of the present invention may have a chemical purity byHigh Performance Liquid Chromatography (HPLC) of greater than about96.0% or greater than about 98.0% or greater than about 99.0% or greaterthan about 99.5%. The amorphous Naloxegol oxalate of the presentinvention may have residual solvents content within the ICH guidelines.

The solid state of the present invention means, unless specifiedotherwise, that the compounds or salts thereof are isolated as solid.The solid state can be in the crystalline, partially crystalline oramorphous.

The solvents referred in the present invention refers, unless otherwisedefined, alcoholic solvents such as methanol, ethanol, n-propanol,isopropanol (2-propanol), n-butanol, isobutanol, and t-butanol; ketonessuch as acetone, propanone, and 2-butanone; esters such as ethylacetate, n-propyl acetate, isopropylacetate and n-butyl acetate and thelike; ethers such as dimethylether, diethylether,methyltertiarybutylether, ethylmethylether, diisopropylether,tetrahydrofuran, and dioxane; halogenated solvents such asdichloromethane, 1,2-dichloroethane and chloroform; hydrocarbons such astoluene, xylene, cyclohexane, n-hexane, and n-heptane; nitrile solventssuch as acetonitrile, and propionitrile; aprotic polar solvents, such asN, N-dimethylformide (DMF), Dimethylsulfoxide (DMSO), and N,N-dimethylacetamide (DMA) or mixtures thereof.

In an aspect, the present invention provides a solid dispersion ofNaloxegol oxalate comprising Naloxegol oxalate in an amorphous and atleast one pharmaceutically acceptable carrier.

The solid dispersion is characterized by X-ray powder diffractionpattern, which is depicted in FIG. 1.

In another aspect, the present invention provides a process for thepreparation solid dispersion of Naloxegol oxalate, which comprises:

-   -   a) dissolving Naloxegol oxalate in a solvent to form a solution;    -   b) adding a pharmaceutically acceptable excipient; and    -   c) isolating amorphous solid dispersion of Naloxegol oxalate.

The solution of Naloxegol Oxalate in step (a) may be provided either bydissolving Naloxegol Oxalate in a suitable solvent or it may be provideddirectly from a reaction mixture containing it that is obtained duringthe course of its manufacture. Suitable solvent that may be used in stepa) may be selected from water; various classes of solvents, such as forexample, alcoholic solvents, ketones, esters, ethers, halogenated,hydrocarbons, nitrile, aprotic polar solvents, or mixtures thereof.

The pharmaceutically acceptable carrier may be added to a reactionsolution containing Naloxegol oxalate to provide solution, dispersion orsuspension. The solvent(s) for providing the solution, suspension ordispersion of Naloxegol oxalate along with one or more pharmaceuticallyacceptable carriers in step b) may be selected from the above listmentioned for providing solution.

Suitable Pharmaceutically acceptable carriers that may be used in stepb) include, but not restricted to water soluble as well as waterinsoluble carriers. The carriers are polyvinylpyrrolidone (povidone),copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose(hypromellose; HPMC), hydroxypropylcellulose (HPC), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer,methylcellulose, ethylcellulose, hydroxypropyl cellulose and itsderivatives, microcrystalline celluloses, polymethacrylates,hypromellose phthalate, hypromellose acetate succinate, celluloseacetate phthalate, carboxymethyl ethyl cellulose and crospovidone. Thepreferable pharmaceutically acceptable carriers are povidone K-30,Copovidone, HPC and HPMC.

The isolation may be obtained by techniques known in the art such asdistillation, evaporation, oven drying, tray drying, spray drying,freeze-drying (lyophilization), fluid bed drying, flash drying, spinflash drying and agitated thin film dryer (ATFD), hot melt extrusion andthe like. Particularly, the solution of step b) is lyophilized to obtainamorphous solid dispersion.

In another aspect, the present invention provides a process for thepurification of 3-O-MEM α-Naloxone, which comprises treatment of3-O-MEM-Naloxone with a base; and optionally isolating the solid of3-O-MEM-Naloxone having purity 99% by HPLC.

The base is selected from inorganic base such as sodium hydroxide,lithium hydroxide, barium hydroxide, barium carbonate, potassiumhydroxide, sodium carbonate, potassium carbonate, sodium hydride and thelike or organic base such as diethyl amine, triethyl amine, diisopropylamine, diisopropyl ethyl amine, N-methyl pyrrolidine, pyridine, and thelike.

After treatment of 3-O-MEM-Naloxone with a base, the reaction mixturemay be extracted into organic solvent and then isolated solid byconcentrated, slurry in solvent or both. The solvent is hydrocarbon, forexample, cyclohexane. The purity of 3-O-MEM-Naloxone is greater than orequal to 99%, preferably greater than about 99.5% by HPLC.

In another aspect, the present invention provides a process for thepreparation of 3-O-MEM α-Naloxol or a pharmaceutically acceptable saltthereof, which comprises stereo selective reduction of 3-O-MEM naloxoneor a salt thereof with reducing agent in presence of solvent andadditive to provide 3-O-MEM α-Naloxol having α-epimer purity is greaterthan about 99.7%.

The present inventors found that the use of small amount of additivesuch as 2-Methoxyethanol during reduction unexpectedly improves the a/13ratio in the range of about 99:1 to 100:0 or to about 99:1 to 99.6:0.4.

The structure of β-epimer of 3-O-MEM Naloxol is:

The reducing agent for stereo selective reduction includes but notlimited to Lithium tri-tert-butoxy aluminium hydride (LTBA). The solventused for the selective reduction may be a alcohol, ether, hydrocarbon,and combinations thereof, an aprotic solvent, or a combination thereof.The temperature used for the reduction is about −20 to 50° C. over aperiod of about 15 minutes to about 1 hour or more. In an embodiment,the temperature used for the addition is about −15 to about 10° C.

The resultant 3-O-MEM α-Naloxol or a pharmaceutically acceptable saltthereof having α-epimer purity is greater than or equal to 99.7% byHPLC.

In another aspect, the present invention provides a process for thepurification of 3-O-MEM α-Naloxol or salt thereof, which comprises:

-   -   a) treatment of 3-O-MEM α-Naloxol with an acid in a solvent to        provide acid addition salt of 3-O MEM α-Naloxol having purity        greater than or equal to 99.5%; and    -   b) optionally, isolating the salt of 3-O MEM α-Naloxol; and    -   c) treatment of the acid addition salt of 3-O-MEM α-Naloxol with        a base to provide —O-MEM α-Naloxol.

The acid is selected from inorganic acid or organic acid. The inorganicacid/organic acids are defined above, preferably, the acid is oxalicacid. The solvent used for step a) is selected from alcohol, ester,ether, nitrile solvent or a combination thereof, preferably alcohol.

The isolation of salt may be performed using suitable techniques such asaddition of anti-solvent, concentration, spray drying and the like.Particularly, the solid is precipitated by the addition of ether solventsuch as methyl t-butyl ether. The resultant solid may be dried undervacuum at 10 to 50° C.

Further, the inventors of the present invention surprisingly found thatpharmaceutically acceptable salt of 3-O-MEM α-Naloxol and its isolationas solid improved the purity and reduced the content of impurities atgreater level. The (3-epimer content and other impurities are reduced toless than about 1% or less than about 0.5% or less than about 0.3%through formation of pharmaceutically acceptable salt of 3-O-MEMα-Naloxol.

The solid of 3-O-MEM-Naloxone and acid addition salt of 3-O-MEMα-Naloxol may be crystalline or amorphous, which are distinct from theprior art i.e. thick liquid or oily mass. Thus, these have differentproperties that make it particularly useful as intermediates for thepreparation of Naloxegol oxalate. The properties are X-ray powderdiffraction (XRPD) pattern, purity by HPLC, Differential ScanningCalorimetry (DSC) and thermogravimetric analysis (“TGA”) curve.

The XRD pattern of 3-O-MEM-Naloxone of the present invention is shown inFIG. 2. The XRD pattern of 3-O-MEM α-Naloxol oxalate of the presentinvention is shown in FIG. 3.

In another embodiment, 3-O-MEM-Naloxone and 3-O-MEM α-Naloxol or apharmaceutically acceptable salt thereof of the present invention may beconverted to naloxegol or a pharmaceutically acceptable salt thereof byconventional process disclosed in the prior art or as described in thepresent application.

The treatment of 3-O-MEM Naloxol salt with a base is performed inpresence of solvent. The solvent includes but are not limited to water,hydrocarbon, halogenated solvents and the like. The base is selectedfrom inorganic base or organic base, which are defined above. Aftercompletion of reaction, the reaction mixture contained 3-O-MEM Naloxolfree base is concentrated and reacted with naloxegol side chain offormula A:

wherein X is leaving group such as mesyl, tosyl, halo, nosyl to provide3-O-MEM Naloxegol.

In another aspect, the present invention provides a process for thepurification of 3-O-MEM naloxegol having purity greater than or equal to95.5%, which comprises:

-   -   i) treating 3-O-MEM naloxegol with acid to provide acid addition        salt of 3-O-MEM naloxegol;    -   ii) optionally isolating the acid addition salt of step (i);    -   iii) treating the acid addition salt of 3-O-MEM naloxegol with a        base to provide 3-O-MEM naloxegol;    -   iv) optionally, isolating 3-O-MEM naloxegol.

The 3-O-MEM naloxegol is treated with an acid such as inorganic ororganic acid, which are defined above, especially the acid is oxalicacid. The solution of acid addition salt is washed with a solvent toremove impurities, which is further treated with a base. The base usedto get pH of about 7.5 to 9.0 is selected from inorganic base or organicbase, as defined above. The base particularly is selected from inorganicbase i.e. sodium carbonate to convert oxalate salt to free base of3-O-MEM naloxegol, which may be used to prepare Naloxegol or it may beisolated as solid.

In an embodiment, the present invention provides 3-O-MEM naloxegoloxalate, which may be formed as in-situ.

The resultant 3-O-MEM naloxegol is deprotected with an acid, which isselected from inorganic or organic acid or source thereof. The acid maybe dry acid such as hydrochloric acid, trifluoro acetic acid or paratoluene sulfonic acid, which may be dissolved in a solvent and used fordeprotection. The deprotection step may be carried out in presence ofantioxidant additive such as butylated hydroxytoluene (BHT) and inpresence of solvent such as water, organic solvent such as alcohol,halogenated solvent, ester; or combination thereof. Preferably, the acidis source of acid i.e. hydrogen chloride in ethyl acetate. The resultantreaction mixture then subjected to pH adjustment of 8 to 9 with a base,preferably inorganic base, to provide Naloxegol free base.

In another aspect, the present invention provides a process for thepurification of Naloxegol or salt thereof, which comprises:

-   -   i) treating Naloxegol with an acid to provide acid addition salt        of naloxegol;    -   ii) optionally, isolating the acid addition salt of Naloxegol;    -   iii) treating the acid addition salt of Naloxegol with a base to        provide pure Naloxegol or salt thereof.

The Naloxegol is treated with an acid such as inorganic acid to obtainacid addition salt of naloxegol. The inorganic acid is selected fromhydrochloric acid, hydrobromic acid, sulfuric acid, and the like. In anembodiment, the present invention provides Naloxegol hydrobromide.

The acid addition salt of Naloxegol is then subjected for pH adjustmentof the reaction mixture to 7 to 9.5 with a base to obtain Naloxegol freebase in pure form. The inventors of the present invention found thedifference in solubility of impurities and Naloxegol base at differentpH and identified selective pH to obtain Naloxegol free base in pureform. The base is selected from sodium hydroxide, sodium carbonate,sodium bicarbonate, potassium hydroxide, potassium carbonate and thelike.

The resultant pure Naloxegol further converted to oxalate salt ofNaloxegol. The naloxegol is reacted with an oxalic acid in presence of asolvent or mixture of solvent selected from ether or ketone or alcohol.

In an embodiment, the process for preparation of Naloxegol oxalate,comprises:

-   -   a) providing a solution of Naloxegol in methyl tert-butyl ether;    -   b) diluting the solution of step a) with n-propyl alcohol;    -   c) adding oxalic acid solution in n-propanol and methyl        tert-butyl ether or mixtures thereof;    -   d) optionally, seeding with naloxegol oxalate; and    -   e) isolating Naloxegol oxalate from step c) or step d).

In another aspect of the present invention, there is provided a processfor the preparation of compound of formula A:

wherein X is leaving group such as mesyl, tosyl, halo, nosyl whichcomprises:

-   -   a) condensation of triethyleneglycol monomethylether        monomesylate with tetraethylene glycolmonobenzyl ether to        provide heptaethylene glycol benzyl methyl ether;    -   b) conversion of the heptaethylene glycol benzyl methyl ether to        compound of formula A.

The reaction of triethyleneglycol monomethylether monomesylate ormonotosylate with tetraethylene glycolmonobenzyl ether is performed inpresence of a base, which is selected from inorganic base or organicbase at a temperature of about 0° C. to about 50° C. The reaction may beconducted in presence of a solvent such as water, alcohol, ether,aprotic polar solvents, hydrocarbon, nitrile, dimethylsulfoxide and thelike. After completion of the reaction, the reaction mixture is washedwith hydrocarbon, preferably, with cyclohexane.

The resultant heptaethylene glycol benzyl methyl ether, further,converted to naloxegol side chain of formula A. The heptaethylene glycolbenzyl methyl ether may be treated with an acid to obtain heptaethyleneglycol monomethyl ether, which may be further reacted with alkyl/arylsulfonyl derivative such as methane sulfonyl chloride, toluene sulfonylchloride, nosyl chloride and the like, or reacted with halogenatingagent such as tetra-n-butylammonium chloride, tetra-n-butylammoniumbromide and the like (or) both one after another to obtain Naloxegolside chain of Formula A.

In an embodiment, the compound of Formula A is22-bromo-2,5,8,11,14,17,20-heptaoxadocosane. The resultant compound of22-bromo heptaoxadocosane has purity greater than or equal to 99.7% byHPLC. The overall process of the present invention is depicted in thefollowing scheme:

In yet another embodiment of the present invention, Naloxegol oxalateprepared according to present invention is converted to itspharmaceutical composition, together with one or more pharmaceuticallyacceptable excipients.

The invention is illustrated with the following examples, which areprovided by way of illustration only and should not be construed tolimit the scope of the invention.

Example 1: Preparation of Amorphous Form Naloxegol Oxalate

Naloxegol oxalate (10 g) was dissolved in purified water (180 ml) and toit Povidone k-30 (10 g) was added at 20-30° C. and was stirred to getsolution. This solution was filtered through hyflo bed to get clearfiltrate. The resulting solution was subjected to lyophilization afterfreezing at −40° C. to afford white solid (19.8 g). The XPRD analysisshows the product is amorphous. Water content is 1.8% w/w.

Residual solvent by GC:methyl t-butylether:146 ppm, n-propanol: 133 ppm.Purity: 99.52% by HPLC; Impurities: 0.04% (3-O-MEM αNaloxegol), 0.05%(PEG-5 naloxol), 0.33% (PEG-6 naloxol), and 0.06% (oxidative dimer).

Example 2: Preparation of Amorphous Form Naloxegol Oxalate

A mixture of Naloxegol Base (2 g, HPLC purity >99.5%), Oxalic acid (0.28g) and Povidone K 30 (1.2 g) were dissolved in a mixture of acetone (188ml) and methanol (12 ml). This solution was filtered through hyflo bedto get clear filtrate, which was subjected to spray drying on BÜCHI minispray dryer B-290 using inlet temperature 80° C., Aspiration 60%. Theresultant solid was dried at 32-37° C. under reduced pressure (≤20 mmHg) till constant weight to get titled compound (2.48 g). The XPRDanalysis showed that the product is amorphous. Residual solvent by GC:Acetone: Not detected; Methanol: 75 ppm.

Example 3: Preparation of 3-O-MEM Naloxone

N,N′-Diisopropylethylamine (21.4 g, 166 mmol) was added slowly to asolution of Naloxone hydrochloride dihydrate (50 g, 125 mmol) indichloromethane (350 ml) at 15-20° C. Purified water (110 ml) added andbiphasic solution was stirred. The layers were separated, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined and concentrated by distillation under reduced pressure ata temperature less than 40° C. till volume reaches to ˜200 ml. and thedichloromethane solution gets dehydrated and dry. Diisopropylethylamine(42 g, 325 mmol) was added to the dichloromethane solution at 4-10° C.Thereafter, solution of MEM Chloride in dichloromethane [36 g, 289 mmolMEM chloride in 100 ml dichloromethane] over 55-65 min at 4-10° C. Afterreaction completion, purified water was added and biphasic solution wasstirred. The layers were separated, and the aqueous layer was extractedwith dichloromethane. Two organic layers were combined and the combinedextract was washed with aqueous sodium hydroxide solution to remove theunreacted Naloxone. The dichloromethane extract was concentrated to anoily residue. Last traces of dichloromethane were removed byco-distilling with small amount of cyclohexane. The residue was stirredfor 6 h with cyclohexane (400 ml) at about 16° C. to complete theprecipitation of product, filtered and washed with cyclohexane (100 ml,24° C.) and then dried at about 40° C. under reduced pressure tillconstant weight. Yield 97.4 g (94.6%). Melting range: 58-62° C. XRPD:FIG. 2. Purity (by HPLC): 99.85%.

Example 4: Preparation of 3-O-MEM Naloxol α-Epimer

Lithium tri-tert-butoxy aluminium hydride (LTBA, 19.93 g, 78.35 mmol)was added to toluene at 0-10° C. 3-O-MEM Naloxone (˜200 ml, prepared bydissolving 25 g, 3-O-MEM Naloxone in a mixture of 187 ml toluene and 1g, 2-Methoxyethanol) was added slowly drop-wise to the above obtainedpre-cooled suspension of Lithium tri-tert-butoxy aluminium hydride intoluene at 0-10° C. After addition, temperature of reaction mass wasraised to 20-30° C. and reaction mass was stirred for 1 h. The reactionwas then stopped by adding ethyl acetate (2.5 ml) to the reaction massat 5-10° C. Further, aqueous ammonium sulphate solution (10 g ammoniumsulphate dissolved in 15 ml DM water) was added to the reaction mass at5-10° C. and stirred for 10 minutes. The reaction mixture was treatedwith hyflo at 20-30° C., filtered through thin hyflo bed and washed withtoluene. Toluene layer was separated and washed with DM water. Thesolvents were removed using rotary evaporator at temperature less than60° C. to give viscous oily liquid (25.1 g, 100% isolated yield).

HPLC analysis indicated that 3-O-MEM Naloxol α-epimer is about 99.4% and3-O-MEM Naloxol β-epimer is about 0.3%.

Example 5: Preparation of 3-O-MEM α-Naloxol Oxalate Salt

3-O-MEM α-Naloxol (5 g) prepared in above example 4 was dissolved inn-propanol (20 ml) at 20-30° C. under nitrogen atmosphere. Oxalic acid(anhydrous) (1.07 g, 11.88 mmol) dissolved in n-propanol (10 ml) wasadded slowly drop-wise to the above at 20-30° C. and stirred for 30minutes. Further methyl t-butyl ether (30 ml) was added slowly drop-wiseto the above at 20-30° C. Oxalate salt precipitated out during addition,which was stirred for 90 minutes at 20-30° C. Product was filtered undernitrogen atmosphere and washed with Methyl t-Butyl ether (20 ml) anddried under vacuum at 20-25° C. to afford white solid (5.02 g). XRPDshown as FIG. 3.

Purity: 99.58% by HPLC; 0.05%(β-3-O-MEM naloxol), 0.04 (6-alphaNaloxol).

Title compound was also prepared by using ethanol instead of n-propanolfor the dissolution of 3-O-MEM α-Naloxol, and MTBE instead of n-propanolfor the dissolution of oxalic acid.

Title compound was also be prepared by using 2-propanol (instead ofn-propanol/MTBE).

Example 6: Preparation of Oxalate Salt

3-O-MEM α-Naloxol (5 g) prepared in above example 4 was dissolved in2-propanol (35 ml) at 20-30° C. under nitrogen atmosphere. Oxalic acid(11.66 mmol) was added to the above reaction mass at 20-30° C. Reactionmass was heated to 60-65° C. to get clear solution. Thereafter reactionmass was slowly cooled to 20-30° C. and stirred at same temperature for30 minutes. Oxalate salt precipitated which was diluted by adding ethylacetate and further stirred at 20-30° C. for 1 h. Product was filteredunder nitrogen atmosphere and washed with mixture of ethyl acetate and2-propanol and dried under vacuum at 20-25° C. to afford white solid(4.4 g).

Example 7: Preparation of Oxalate Salt

3-O-MEM α-Naloxol (5 g) prepared in above example 4 was dissolved inethyl acetate (50 ml) at 20-30° C. under nitrogen atmosphere which wascooled to 10-15° C. Oxalic acid (1.28 g, 14.3 mmol) dissolved in ethylacetate (25 ml) was added slowly drop-wise to the above at 10-15° C.Oxalate salt precipitated out during addition, which was stirred for 60minutes at 10-15° C. Product was filtered under nitrogen atmosphere andwashed with ethyl acetate (50 ml) and dried under vacuum at 20-25° C. toafford white solid (5.9 g).

Example 8: Preparation of 3-O-MEM Naloxegol

Sodium carbonate (3.14 g) was dissolved in water (50 ml) and to thissolution was added toluene (45 ml) and 3-O-MEM-α-Naloxol oxalate (10 g,19.7 mmol) at 15-20° C. The resulting solution was stirred at 20-30° C.for 30 minutes, and the organic layer separated and aqueous layer wasextracted with toluene. The combined organic layer was washed withwater. Butylated hydroxy toluene (BHT) (0.4 g) was added to the organiclayer and then concentrated at a temperature less than 60° C. tillvolume reaches to ˜20 ml. In another reaction vessel sodium hydride (1.5g, 64.6 mmol) was added into a mixture of DMF (4 ml) and toluene (16 ml)at 5-10° C. To this slurry was added diluted solution of3-O-MEM-α-Naloxol base (˜20 ml) diluted with DMF (2 ml) in 30 minutesand then stirred for 30 minutes under nitrogen atmosphere. Thereafter,added a solution of 22-Bromo-heptaoxadocosane (30 g, 74 mmol) in amixture of toluene (24 ml) and DMF (12 ml) for 3-4 h at 8-16° C. Afterreaction completion, aqueous ammonium chloride (15% w/w, 100 ml) wasadded to the reaction mass and extracted with Toluene (70 ml). Thecombined organic extracts were washed with brine (30 ml). Thereafterwashed organic layer diluted with purified water and then cooled to15-20° C. This solution was acidified with aqueous oxalic acid solution(10% w/w) at 15-20° C. Organic layer separated and the aqueous layer waswashed with dichloromethane. The resulting aqueous layer containing3-O-MEM naloxegol oxalate salt was added dichloromethane (50 ml)followed by neutralization with aqueous sodium carbonate solution (20%w/w) and stirred for 20 minutes at 20-30° C. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane. Thecombined organic layer was concentrated by distillation under reducedpressure to afford 3-O-MEM

Naloxegol (13 g) as a pale yellow colour liquid.

Purity: 95.76% by HPLC; Impurities: 1.44 (3-O-MEM alpha Naloxol) and0.83% (6,14-dialkylated 3-O-MEM Naloxegol).

Title compound was also prepared by using 22-OMs-heptaoxadocosaneinstead of 22-Bromo-heptaoxadocosane in a manner similar to thatdescribed above.

Example 9: Preparation of Naloxegol Base

Hydrogen chloride (˜6% w/w) solution in ethyl acetate (31 g, 51 mmol)was slowly added to the solution of 3-O-MEM Naloxegol (10 g, 13.5 m mol)in ethyl acetate (20 ml) containing Butylated hydroxy toluene (BHT) (0.1g) at 10-15° C. and the mixture was stirred for ˜90 min at 10-15° C.After reaction completion, purified water (50 ml) was added at 10-20° C.Organic layer was separated and the aqueous layer was washed with ethylacetate (20 ml). The aqueous solution containing Naloxegol hydrochloridewas neutralized by addition of aqueous sodium carbonate solution (20%w/w) and the product was extracted with dichloromethane (80 ml). Thedichloromethane solution was concentrated by distillation under reducedpressure to get pale yellow colored viscous liquid/residue. The residuewas diluted with purified water (30 ml) and then acidified by additionof aqueous hydrobromic acid solution (˜20% w/w) at 10-20° C. The aq.solution containing product as hydrobromide salt is repeatedly washedwith dichloromethane. The washed aqueous solution containing Naloxegolhydrobromide is neutralized with aq. sodium carbonate solution,extracted with dichloromethane, washed with water and then concentratedto afford Naloxegol (6.9 g) as a pale yellow colour viscous liquid.

Example 10: Preparation of Naloxegol Oxalate

Naloxegol (5 g) was dissolved in MTBE (40 ml) and n-propanol (5 ml). Thesolution of Oxalic acid (0.7 g) prepared in MTBE (30 ml) and n-propanol(2 ml) was added slowly to the Naloxegol base solution. Naloxegoloxalate was precipitated during addition and product slurry was furtherstirred for about 3 hours. It was then cooled to 12-15° C. and furtherstirred for about 45 minutes. Product was filtered under nitrogenatmosphere and was washed with MTBE and dried under vacuum at 25-30° C.to afford white solid (5.0 g).

Purity: 98.58% by HPLC; Impurities: 0.03% (3-O-MEM-naloxegol), 0.05%(dialkylated Naloxegol), 0.08% (β-epimer), 0.64% (PEG-8 Naloxegol),0.37% (PEG-6 Naloxegol), 0.08% (PEG-5 naloxegol) and 0.07% (PEG-3naloxegol).

Example 11: Preparation of Naloxegol Side Chain A). Preparation ofTriethylene Glycol Monomethyl Ether Monomesylate:

Triethylene glycol monomethyl ether (200 g; 1.21 moles) was dissolved inmethylene chloride (800 ml). To this solution added Triethylamine (148g; 1.46 moles) and cooled to 0-5° C. The solution of methanesulfonylchloride (167.4 g; 1.46 moles) prepared in methylene chloride (260 ml)was added slowly to the above solution and stirred for 1 hour at 20-30°C. The mixture was then cooled 5-10° C. and water (400 ml) was added.The layers were separated and the organic layer was washed with aq.NaHCO₃ solution followed by with water and then concentrated bydistillation under reduced pressure to afford title compound (250 g).Purity by GC: 98.58%; Impurities: PEG 3 monomethyl ether: 0.11%; PEG 2dimesylate: 0.45% and PEG 3 monochloro monomethyl ether: 0.06%

B). Preparation of Tetraethylene Glycol Monobenzyl Ether:

Sodium hydroxide powder (47.5 g; 1.18 moles) was slowly added totetraethylene glycol (460 g; 2.37 moles) at 20-25° C. Benzyl chloride(100 g; 0.79 moles) was added slowly to the mixture and stirred for 6hours. Water (1 L) was added slowly and adjusted pH of the reaction to9.5-10 with aq. HCl solution. The aqueous layer was extracted withcyclohexane to remove the tetraethyleneglycol dibenzylether. The aqueouslayer again was extracted with toluene and washed the organic layer withaq. NaCl solution and then concentrated to afford titled compound (135g). HPLC purity: 99.15%; Impurities: PEG 3 monobenzyl ether:0.09%; PEG 5monobenzyl ether: 0.13% and PEG 4 dibenzyl ether:0.21%.

C). Preparation of Heptaethylene Glycol Monomethyl Ether:

Potassium hydroxide (40 g; 0.71 moles) was added to THF (600 ml) andthen added tetraethylene glycol monobenzyl ether (100 g; 0.352 moles),raised the temperature to 60-70° C. and stirred for 30 min. The solutionof triethylene glycol monomethyl ether monomesylate (90 g; 0.371 moles)prepared in THF (100 ml) was added slowly to the above solution andstirred for 24 hours at reflux. The reaction mixture was concentratedunder reduced pressure and added water. The concentrated aq. reactionmass was extracted with cyclohexane followed by toluene to remove thenon polar impurities. The separated organic layer washed with aq. sodiumchloride solution and then concentrated to afford heptaethyleneglycolmonobenzyl monomethylether (120 g) as a reddish brown color residue(HPLC purity 96.2%).

The above concentrate mass was dissolved in ethanol and treated withcarbon. To the filtrate conc.HCl (1.2 ml) was added and then taken thesolution in an autoclave and 10% palladium on carbon paste (2.50 g,contains ˜50% w/w water) was added and used 5-6 Kg/Cm2 hydrogen pressurefor 4 hours. Sodium bicarbonate (3.6 g) was added to neutralize thehydrochloric acid, filtered through hyflo pad, washed the residue withethanol. The combined ethanol filtrate was concentrated to yellow oilyresidue. The concentrated mass was dissolved in water and washed withethyl acetate. Two layers were separated and the aqueous layer was againextracted with methylene chloride and washed organic layer with purifiedwater and concentrated under reduced pressure to afford titled compoundas a pale yellow liquid (54 g). Purity by GC: 99.0%; Impurities:PEG 6monomethyl ether: 0.24%; PEG 6 dimethyl ether:0.27%; PEG 5 monomethylether:0.04%; PEG 8 monomethyl ether: 0.14%.

D) Preparation of 22-Bromo-2,5,8,11,14,17,20-Heptaoxadocosane:

The above obtained compound (200 g; 0.588 moles) was dissolved inmethylene chloride (700 ml) and cooled to 0-5° C. To this solutiontriethyl amine (92 g; 0.91 moles) was added and then solution ofMethanesulfonyl chloride (84 g; 0.733 moles) prepared in methylenechloride (240 ml) was added slowly to the above solution and stirred for30 min. The temperature was raised to 20-30° C. and stirred for 1 hour,and then cooled 5-10° C. The reaction mixture was diluted withdichloromethane, followed by water, organic layer was separated andwashed with aq. sodium bicarbonate solution and with water, and thenconcentrated under reduced pressure to afford Heptaethylene glycolmonomethylether monomesylate (240 g) as a yellow color liquid. Theconcentrated residue was dissolved in toluene (1000 ml) and addedTetra-n-butylammonium bromide (197 g; 0.611 moles) at 20-30° C. Thereaction mass was heated to 80-85° C. and maintained for 2 hours. Themixture was cooled and water was added, the organic layer was separated,aq. solution was extracted with toluene. The combined organic layerswere washed with aqueous sodium chloride solution and then concentratedthe toluene layer under reduced pressure to afford titled compound as apale yellow color liquid (190 g).

GC purity: 98-99%; Impurities: PEG 5 Monobromo Monomethyl Ether:0.17%;

PEG 6 Monobromo Monomethyl Ether: 0.25%; PEG 8 Monobromo Monomethylether:0.18%; PEG7 Monochloro Monomethyl Ether:0.5%.

We claim:
 1. A process for the preparation of Naloxegol or salt thereof,which comprises: a) stereoselective reduction of 3-O-MEM naloxone orsalt thereof, with reducing agent in presence of an additive to provide3-O-MEM α-Naloxol; b) optionally, purification of 3-O-MEM α-Naloxol withan acid and a base; c) reacting 3-O-MEM α-Naloxol with side chain ofFormula A:

wherein X is leaving group such as mesyl, tosyl, halo, nosyl to provide3-O-MEM Naloxegol; d) optionally, purification of 3-O-MEM Naloxegol withan acid and a base; e) converting the 3-O-MEM Naloxegol to Naloxegol orsalt thereof.
 2. The process as claimed in claim 1, wherein the reducingagent is Lithium tri-tert-butoxy aluminium hydride (LTBA).
 3. Theprocess as claimed in claim 1, wherein the additive is 2-Methoxyethanol.4. The process as claimed in claim 1, wherein the acid is oxalic acidand base is sodium carbonate.
 5. The process as claimed in claim 1,wherein the purification of 3-O-MEM α-Naloxol comprises: a) treatment of3-O-MEM α-Naloxol with an acid to provide acid addition salt of 3-O MEMα-Naloxol; b) isolating the salt of 3-O MEM α-Naloxol containing lessthan 1% of β-epimer; and c) treatment of the acid addition salt of3-O-MEM α-Naloxol with a base to provide 3-O-MEM α-Naloxol.
 6. Theprocess as claimed in claim 5, wherein the acid is selected from organicacid and the base is selected from inorganic base.
 7. The process asclaimed in claim 1, wherein the side chain of Formula A is selected from22-bromo-heptaoxadocosane and 22-OMs-heptaoxadocosane.
 8. The process asclaimed in claim 1, wherein the purification of 3-O-MEM naloxegolcomprises treating 3-O-MEM naloxegol with an acid and a base to provide3-O-MEM Naloxegol having purity greater than or equal to 95.5%.
 9. Theprocess as claimed in claim 8, wherein the acid is oxalic acid and baseis sodium carbonate.
 10. The process as claimed in claim 1, wherein the3-O-MEM naloxegol is deprotected with an acid to obtain Naloxegol.
 11. Aprocess for the purification of 3-O-MEM α-Naloxol, which comprises: a)treatment of 3-O-MEM α-Naloxol with an acid in a solvent to provide acidaddition salt of 3-O MEM α-Naloxol; b) isolation of the acid additionsalt of 3-O MEM α-Naloxol containing less than 1% of β-epimer; and c)treatment of 3-O-MEM α-Naloxol with a base to provide 3-O-MEM α-Naloxol.12. The process as claimed in claim 11, wherein the acid addition saltof 3-O-MEM α-Naloxol is 3-O-MEM α-Naloxol oxalate.
 13. The process asclaimed in claim 12, wherein 3-O-MEM α-Naloxol oxalate is crystalline.14. The process as claimed in claim 11, wherein the purity of 3-O-MEMα-Naloxol is about 99% or greater.
 15. The process as claimed in claim11, wherein the acid is selected from organic acid and the base isselected from inorganic base.
 16. A process for the preparation of3-O-MEM α-Naloxol, which comprises stereoselective reduction of 3-O-MEMnaloxone or salt thereof with a reducing agent in presence of additiveto provide 3-O-MEM α-Naloxol.
 17. The process as claimed in claim 16,wherein the reducing agent is Lithium tri-tert-butoxy aluminium hydride(LTBA).